Field of the Invention
The present invention describes the use of chemical compounds in the preparation of a pharmaceutical composition that acts by inhibiting the phosphorylase uridine enzyme. Particularly, the present invention comprises the use of the compounds of formula I or II, alone or in combination with at least one antineoplastic for the preparation of a pharmaceutical composition that acts by inhibiting the phosphorylase uridine enzyme, wherein the inhibition acts, for example, in the antineoplastic effectivity increase and in the side effects reduction caused by the antineoplastic administration. The present invention is found in the fields of chemistry, pharmacy and medicine.
Prior Art
The human phosphorylase uridine enzyme (EC 2.4.2.3) is one of the promising targets for the study and development of new chemical compounds with capacity of increasing uridine (Urd) endogenous levels by inhibiting the catalyzed chemical reaction by the protein. A class of inhibitor compounds of this enzyme is the one of the derivatives of 6-hydroxy-2-pyridones, which have been tested regarding the several pathologies, including neurodegenerative, heart and neoplasia diseases. However, the technical challenges remaining for achieving the structures of this compounds class, in special compounds that present an increased specific enzymatic inhibition and, at the same time, act in a combined manner with other drugs, in special the drugs for treating cancer, which are known by their several undesirable side effects, as the weight loss and inflammatory toxic reactions, as the mucositis.
Among the compounds known for oncological treatment, it is included the 5-fluorouracil, which main side effects caused are: alopecia, weight loss, diarrhea and mucositis, this latter either intestinal as oral. Due to these side effects, the patients stop their treatments because the severe pains and because the feeding impossibility due to oral ulcers. It is in this context that the search for new combined chemotherapies regimens become important.
The document of Stopper et al (“Combination of the chemotherapeutic agent 5-fluorouracil with an inhibitor of its catabolism results in increased micronucleus induction”, Biochem Biophys Res Commun. 1994 Sep. 15; 203(2):1124-30) discloses that the necessary concentration of 5-fluorouracil may be reduced on half for achieving the genotoxic effect in the presence of the chemotherapeutic 2,6-dihydroxypiridine. It is also disclosed that the combined application of 5-fluorouracil and one inhibitor, 2,6-dihydropyridine, for example, it reduces the side effects of the antineoplastic by reducing the chemotherapeutic effective dose.
The present invention differs from this document by the fact that it discloses the use of compounds originated from 6-hydroxy-2-pyridones different from that disclosed in Stopper et al. and which action mechanism is also different, by having as target the human phosphorylase uridine enzyme (hUP, EC 2.4.2.3). The present invention also differs from this document by enabling the amount reduction of 5-fluorouracil that is converted to 5-fluorouridine and 5-fluoro-uridine monophosphate.
The search in the patent literature indicated some relevant documents that will be described below.
The document U.S. Pat. No. 5,155,113 discloses that the combined therapy of 5-fluorouracil (or some compound able to produce in vivo 5-fluorouracil) with one derived from pyridine, as defined in U.S. Pat. No. 5,155,113, would be able of potentiate the anticancer activity of the 5-fluorouracil.
The present invention differs from this document by the fact of proposing the use of different compounds from class 6-hydroxy-2-pyridones and that are used in a combined therapy with anti-tumor drugs, as the 5-fluorouracil. In addition, the action mechanism of the compounds used in the present invention (inhibiting the phosphorylase uridine) is different from those disclosed in U.S. Pat. No. 5,155,113.
The document U.S. Pat. No. 4,613,604 discloses a pharmaceutical composition having phosphorylase uridine enzyme inhibitors, wherein they increase the anti-tumor effectivity of pyrimidine nucleotides, as the 5-fluorouracil and that do not interfere with the normal cells growth of the patient.
The present invention differs from this document by the fact of presenting inhibitor compounds of the human phosphorylase uridine with structure different from those described in the document U.S. Pat. No. 4,613,604. While the document U.S. Pat. No. 4,613,604 discloses compounds originated from pyrimidines, the present invention discloses derivatives from pyridines. In addition, the document U.S. Pat. No. 4,613,604 does not disclose neither suggests a solution for the side effects caused by antineoplastic.
The document U.S. Pat. No. 5,567,689 discloses methods and pharmaceutical compositions for increasing uridine levels in the plasma and intracellular, with compounds dilazep, hexobendine, L-uridine; L-2′-3′-dideoxiuridine, and D-2′,3′-dideoxiuridine.
The present invention differs from this document by the fact of presenting the use of distinct compounds and the document U.S. Pat. No. 5,567,689 does not disclose or suggest the combination of these compounds with antineoplastic.
In this way, there is the need of searching for compounds having increased capacity of inhibiting the phosphorylase uridine enzyme, inhibiting this may prevent or reduce the amount of side effects caused by antineoplastic, or, further, be used in the therapeutic of several diseases in which the uridine endogenous increase by being a therapeutic alternative for current treatments.
According to searched literature, documents anticipating or suggesting the present invention teachings were not found, in a way that the solution here proposed has novelty and inventive activity against the state of the art.